Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into a variety of cell types. Bortezomib, the first approved proteasome inhibitor used for the treatment of multiple myeloma (MM), has been shown to induce osteoblast differentiation, making it beneficial for myeloma bone disease. In the present study, we aimed to investigate the effects and underlying mechanisms of bortezomib on the cell cycle during osteogenic differentiation. We confirmed that low doses of bortezomib can induce MSCs towards osteogenic differentiation, but high doses are toxic. In the course of bortezomib‐induced osteogenic differentiation, we observed cell cycle exit characterized by G₀/G₁ phase cell cycle arrest with a significant reduction in cell proliferation. Additionally, we found that the cell cycle exit was tightly related to the induction of the cyclin‐dependent kinase inhibitors p21^Cip1 and p27^Kip1. Notably, we further demonstrated that the up‐regulation of p21^Cip1 and p27^Kip1 is transcriptionally dependent on the bortezomib‐activated ER stress signalling branch Ire1α/Xbp1s. Taken together, these findings reveal an intracellular pathway that integrates proteasome inhibition, osteogenic differentiation and the cell cycle through activation of the ER stress signalling branch Ire1α/Xbp1s.

中文翻译：

---

硼替佐米诱导的间充质干细胞成骨分化过程中的细胞周期退出是由 Xbp1s 上调的 p21Cip1 和 p27Kip1 介导的。

间充质干细胞 (MSC) 是能够分化成多种细胞类型的多能细胞。Bortezomib 是第一个被批准用于治疗多发性骨髓瘤 (MM) 的蛋白酶体抑制剂，已被证明可诱导成骨细胞分化，使其有益于骨髓瘤骨病。在本研究中，我们旨在研究硼替佐米对成骨分化过程中细胞周期的影响和潜在机制。我们证实低剂量的硼替佐米可以诱导 MSCs 向成骨分化，但高剂量是有毒的。在硼替佐米诱导的成骨分化过程中，我们观察到以 G ₀ /G _{1 为}特征的细胞周期退出细胞周期停滞期，细胞增殖显着减少。此外，我们发现细胞周期退出与细胞周期蛋白依赖性激酶抑制剂 p21 ^Cip1和 p27 ^Kip1的诱导密切相关。值得注意的是，我们进一步证明 p21 ^Cip1和 p27 ^Kip1的上调在转录上依赖于硼替佐米激活的内质网应激信号分支 Ire1α/Xbp1s。总之，这些发现揭示了一种通过激活内质网应激信号分支 Ire1α/Xbp1s 来整合蛋白酶体抑制、成骨分化和细胞周期的细胞内途径。